Risk of Gastrointestinal Bleed and Endoscopic Procedures on Antiplatelet and Antithrombotic Agents Partha Pal, Manu Tandan, Duvvuru Nageshwar Reddy

Published online: 2019-09-16

Review Article Risk of Gastrointestinal Bleed and Endoscopic Procedures on Antiplatelet and Antithrombotic Agents Partha Pal, Manu Tandan, Duvvuru Nageshwar Reddy

Department of Medical The use of antiplatelet and antithrombotic agents has increased hand in hand with Gastroenterology, Asian the number and complexity of endoscopic procedures. Hence, the endoscopists Institute of Gastroenterology, Hyderabad, Telangana, India are often faced with considering endoscopy in patients on these agents. In this setting, to make informed decision, four key aspects are need to be considered. Abstract The type of antithrombotic or antiplatelet agent used and its characteristics, risk of thromboembolic events (which can lead to ischemic stroke or acute coronary syndrome, both of which carry high morbidity) due to withholding the drug, risk of bleeding (increases with invasiveness of procedure), and timing of procedure (elective or urgent) are the key factors to consider. We aim to discuss the risk of gastrointestinal bleed and endoscopic procedures on antiplatelet and antithrombotic agents focusing on Indian context based on recent Asia‑pacific guidelines along with other existing guidelines. Keywords: Antiplatelets, antithrombotic agents, endoscopy, gastrointestinal bleeding

Introduction is taking. The knowledge of mechanism of action, astrointestinal (GI) bleed is one of the most onset and offset of action, pharmacokinetics, drug common medical emergencies in day‑to‑day interactions, and risk of bleeding with each agent is G essential for periendoscopic management of patients practice. With increase in age and comorbidities,

on antiplatelet or antithrombotic agents. The timing of the use of antithrombotic agents (antiplatelet and discontinuation before endoscopy and resumption after anticoagulant agents) is widely prevalent, and this endoscopic hemostasis is discussed in detail later in the has added an additional dimension in the management manuscript. Summary of properties of oral antiplatelets of patients with GI bleed or those requiring a and anticoagulant agents is given in Table 2.[1,2] therapeutic endoscopic procedure. A balance between the risk of procedural hemorrhage and Host’s Risk of Thrombosis the risk of thromboembolism on discontinuation of Risk of thrombosis on stopping antithrombotic agents antithrombotic agents is essential. Knowledge of drug depends on underlying cardiovascular/cerebrovascular/ pharmacokinetics and urgency of the procedure are the peripheral vascular status or presence of prothrombotic other facts to consider [Table 1]. A close cooperation states. This determines the risk of thrombosis and is essential between physician, cardiologist, and the timing of resumption of antiplatelets or antithrombotic endoscopist for the proper management of such patients agents. who require GI endoscopy. Types of Antiplatelet or Antithrombotic Address for correspondence: Dr. Partha Pal, Department of Medical Gastroenterology, Asian Institute Drug of Gastroenterology, 6‑3‑661, Somajiguda, Hyderabad, Telangana, India. The endoscopist should inquire about the drugs E‑mail: [email protected] (antiplatelet and antithrombotic agents) that the patient This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows Access this article online others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical Quick Response Code: terms. Website: www.jdeonline.in For reprints contact: [email protected]

How to cite this article: Pal P, Tandan M, Reddy DN. Risk of gastrointestinal DOI: 10.4103/jde.JDE_10_19 bleed and endoscopic procedures on antiplatelet and antithrombotic agents. J Dig Endosc 2019;10:XX-XX.

Table 1: Key factors to consider for periprocedural MACEs was stable after 6 months in both DES and [4] management of patients on antiplatelets and BMS. anticoagulants undergoing endoscopy On the other hand, the British Society of Drug factors Host’s risk of Host’s risk Timing of Gastroenterology/European Society of GI Endoscopy thrombosis of bleeding procedure (BSG‑ESGE) and the American Society of Mechanism Cardiovascular status Ultrahigh‑risk Urgent of action (acute coronary procedure Gastroenterology (ASGE) guidelines are based on syndrome or stable the 2014 American College of Cardiology/American CAD) Heart Association guidelines that stated that the risk of Dose and Cerebrovascular status noncardiac surgery is high in patients with BMS placed efficacy within 1 month or DES placed within 12 months.[5] The Duration of Peripheral vascular High‑risk American College of Chest Physicians recommends action status procedure delaying noncardiac surgery for 6 weeks for BMS and Renal/hepatic Prothrombotic states Elective [6] clearance 6 months in case of DES. Drug Prosthetic valve Risk of thrombosis in prothrombotic states interactions Different societies have stratified patients according to Onset of Atrial fibrillation Low‑risk their risk of thromboembolism during discontinuation action procedure of warfarin. The criteria for bridging therapy differ in Risk of Structural cardiac bleeding valve disease different guidelines. In ESGE guidelines, nonvalvular History of venous atrial fibrillation (AF) was considered low risk thumbs‑embolism irrespective of their CHA2DS2VASc score (congestive CAD=Coronary artery disease heart failure – 1 point, hypertension – 1 point, age ≥75 years – 2 points, diabetes mellitus –1 point, Risk of thrombosis post coronary stent/coronary stroke – 2 points, vascular disease – 1 point, age artery disease/cerebrovascular or peripheral 65–74 years – 1 point, female sex – 1 point, and total arterial disease points – 9) as there is a significantly higher risk of The risk of stent thrombosis due to discontinuation bleeding with bridging therapy compared to no bridging of antithrombotic agents can be very high, high, and therapy in RE‑LY trial.[7] However, the data could not moderate/low based on timing of discontinuation be extrapolated to patients with mitral stenosis or after acute coronary syndrome/percutaneous coronary CHA2DS2VASc score >5 due to small number of such intervention (ACS/PCI): <6 weeks, 6 weeks–6 months, patients. The role of bridge therapy in AF with mitral and >6 months, respectively, according to APAGE/ [3] stenosis is also controversial, and the result of BRIDGE APSDE guidelines. Stable coronary artery disease, trial which showed foregoing bridging therapy is cerebrovascular disease, and peripheral arterial noninferior to periprocedural heparin bridging to disease also fall under low‑risk category. For very prevent arterial thromboembolism with lower risk high‑risk category, the procedure should be deferred, of bleeding.[8] In ESGE guidelines, AF with mitral and for high‑risk cases, defer procedure if possible stenosis is regarded as high risk of thromboembolism, to >6 months. For low‑risk cases, the procedure should but in APAGE/APSDE guidelines, it is regarded as low not be deferred. The difference between high and low risk with no need for bridging therapy. As patients of risk is that for discontinuing antithrombotic agents, nonvalvular AF with CHA2DS2VASc score >5 have high‑risk patients need heparin‑bridging therapy. These a high risk of thromboembolism, bridging therapy has have been detailed in Table 3. been recommended by APAGE/APSDE guidelines. In This recommendation is based on a recent retrospective contrast, the cutoff of the same score is >2 in ASGE [3,9,10] cohort study based on data of 42,000 patients guidelines. undergoing surgery within 24 months of placement of Although there are differences in the various guidelines, coronary stent. The incidence of major adverse cardiac the basic concept is either there is a high or low risk events (MACEs) after surgery within 6 weeks, 6 weeks of thromboembolism in the absence of anticoagulant, to 6 months, 6–12 months, and >12–24 months was and the high‑risk patients need bridging therapy by 11.6%, 6.4%, 4.2%, and 3.5%, respectively. MACE unfractionated heparin (UFH) (ASGE and APAGE/ incidence was not different between drug‑eluting APSDE) or low‑molecular‑weight heparin (LMWH) stent (DES) and bare metal stent (BMS), and risk of (BSG/ESGE). The most recent guidelines are by

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Table 2: Summary of properties of commonly used oral antiplatelets and anticoagulant agents Mechanism of Dose Efficacy Onset of Duration of Renal/hepatic Drug Risk of action action action clearance interaction bleeding Aspirin Irreversible 75-300 mg/day, 25% reduction 5-30 min Antiplatelet Liver 90%, renal Acetazolamide 1%-3% per inhibition 160 mg/day in the risk of effect 10% and alcohol year of platelet for complete cardiovascular persists for increases the cyclooxygenase inhibition of death, MI, or 7-10 days toxic effects (COX)‑1 platelet COX‑1 stroke of salicylates Clopidogrel Inhibit Clopidogrel‑75 Compared Onset of Antiplatelet Renal and CYP2C19 Combining and ADP‑ induced mg/day, loading with aspirin, action effect hepatic inhibitor. clopidogrel Prasugrel platelet dose ‑ 300 mg; clopidogrel 4‑6 h, persists up to clearance 50% Concomitant with aspirin aggregation Prasugrel ‑10 reduces prasugrel 5-7 days each use of increases by irreversibly mg/day, 5 mg/ the risk of has more omeprazole risk of blocking day for <60 kg cardiovascular rapid onset can reduce major P2Y12 and age >75 kg death, MI, and of action antiplatelet bleeding to stroke by 8.7%, effect about 2% Prasugrel is per year ten times more potent than clopidogrel Warfarin Vitamin K Starting dose >60% Delayed Half‑life Metabolized Amiodarone, Major antagonist is 5-10 mg, reduction in until 25-60 h, by CYP2C9 azoles, bleeding interferes lower dose thromboembolic 5 days as mean 40 (major) and clopidogrel, risk is synthesis of with CYP2C9 events when reduced h, duration CYP3A4 fluoxetine, <5%/year the Vitamin or VKORC1 maintained levels of of action (minor) isoniazid, if INR is K‑dependent polymorphisms in therapeutic factor II 2-5 days pathways. metronidazole, 2-3, Risk clotting factors: range and X are metabolites furosemide, of major II, VII, IX, achieved excreted in stool valproate can bleeding and X by that and urine increase risk increases time of bleeding with with warfarin INR >4, especially in elderly Dabigatran Direct 150 mg twice Noninferior to 1-4 h 24 h, 80% Interaction 39% Thrombin daily, half well‑managed Half‑life renal ‑dialyzable, with drugs reduction inhibitor dose in renal Vitamin K 11-17 h, Contraindicated metabolized in the risk insufficiency antagonist Depends on in CrCl <30 ml/ by of major therapy for CrCl min and CTP‑C P‑glycoprotein bleeding, treatment of Cirrhosis (P‑gp) a 63% VTE: In pooled pathways reduction in analysis of intracranial trials, bleeding Apixaban Factor Xa 5 mg twice recurrent fatal 1-4 h 24 h, 25% renal, not Interaction and a 64% inhibitor daily, half dose and nonfatal Half‑life dialyzable, with drugs reduction if age >80 years, VTE occurred 12 h Contraindicated metabolized in fatal Body weight in 2.0% of in CTP‑C by CYP3A4/ bleeding <60 kg, Cr >1.5 those given Cirrhosis, P‑gp compared g/dl direct oral caution in to warfarin anticoagulants CTP‑A and B but higher Rivaroxaban Factor Xa 20 mg once compared with 1-4 h 24 h, 66% renal‑ not Interaction rate of GI inhibitor daily, 15 mg 2.2% of those Half‑life dialyzable, with drugs bleeding as once daily with given a Vitamin 7-11 h Contraindicated metabolized unabsorbed a creatinine K antagonist in CTP‑B and C by CYP3A4/ active drug clearance of 15- Timing of Cirrhosis P‑gp in the gut 49 mL/min discontinuation exacerbates of DOACs bleeding before endoscopy: 2 days for all

Contd...

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Table 2: Contd... Mechanism of Dose Efficacy Onset of Duration of Renal/hepatic Drug Risk of action action action clearance interaction bleeding Edoxaban Factor Xa 60 mg daily, 30 DOACs except 1-4 h 24 h, 35% renal ‑ not Interaction Antidote inhibitor mg daily with dabigatran Half‑life dialyzable, with drugs Activated CrCl of 15-50 For dabigatran 9-11 h can be used metabolized charcoal mL/min, body it depends on with caution in by P‑gp within 3 h weight <60 kg CTP‑C CrCl Idaru or receiving CrCl ‑ 30‑50:4d ‑cizumab potent P‑gp and dialysis inhibitors such CrCl ‑ 50‑80:3d for only as dronedarone CrCl ‑ > 80: 2d dabigatran or verapamil COX=Cyclooxygenase, MI=Myocardial infarction, CYP=Cytochrome P 450, VKORC1=Vitamin K epoxide reductase complex, P‑gp=P‑glycoprotein, CrCl=Creatinine clearance, DOACs=Direct oral anticoagulants, VTE=Venous thromboembolism, CTP=Child- Turcott-Pugh

Table 3: Thrombotic risk category and antithrombotic therapy management in elective endoscopic procedures TE risk Low High Very high ACS/PCI >6 months stable CAD, cerebrovascular disease, ACS/PCI 6 weeks-6 months ACS/PCI <6 weeks peripheral vascular disease Deferring procedure Do not defer Defer>6 months Defer procedure Aspirin Continue aspirin Continue aspirin P2Y12 stopping Stop P2Y12 for 5 days Stop P2Y12 for 5 days P2Y12 resumption Resume P2Y12 after adequate hemostasis Resume P2Y12 after adequate hemostasis Warfarin stopping Stop warfarin 5 days before Stop warfarin 5 days before Warfarin resumption Resume warfarin after adequate hemostasis Resume warfarin after adequate hemostasis

Bridging therapy No heparin bridging Heparin bridging DOAC stopping Stop DOAC 2 days before Stop DOAC 2 days before DOAC resumption Resume DOAC after adequate hemostasis Resume DOAC after adequate hemostasis Bridging therapy No heparin bridging Heparin bridging ACS=Acute coronary syndrome, PCI=Percutaneous coronary intervention, DOAC=Direct‑acting oral anticoagulant, CAD=Coronary artery disease

Table 4: Risk stratification for discontinuation of Host’s risk of bleeding warfarin therapy with respect to the requirement of Incidence of gastrointestinal bleeding in the setting of heparin bringing acute coronary syndrome High risk for TE Low risk for TE Risk of bleeding from any site in the setting of (bridging therapy required) (bridging therapy not required) ACS is between 3.2% and 9.1%, and majority of VTE <3 months VTE >3 months the life‑threatening bleed are GI. Reported rates of Prosthetic valve with Nonvalvular AF with GI bleeding in the setting of ACS are estimated to AF, nonvalvular AF with CHA2DS2‑VASc ≤5, xenograft CHA2DS2‑VASc >5 heart valve, AF with mitral be 1%–3%, and those who develop GI bleed have a [11‑15] stenosis 4–7‑fold increased risk of mortality. Abbas et al. [16] Metallic mitral valve Metallic aortic valve reported bleeding rate of 2.3% and mortality of 10%. Severe thrombophilia Nonsevere Increasing age, female sex, previous bleeding, and renal (protein C, protein S and thrombophilia (heterozygous impairment are predictors of bleeding from any site after antithrombin III deficiency, factor V deficiency or PCI according to GRACE study, whereas risk factors antiphospholipid antibody, prothrombin gene mutation) for GI bleed are age, prior history of ulcer, Helicobacter multiple abnormalities) pylori infection, nonsteroidal anti‑inflammatory drugs TE=Thromboembolism, VTE=Venous thromboembolism usage, sepsis, and mechanical ventilation.[11,14] APAGE/APSDE which has stratified patients according Among the antiplatelets, aspirin is ulcerogenic whereas to the need for bridging therapy which is required clopidogrel is not. Hence, risk of GI bleeding with obviously in high‑risk patients [Table 4].[3,9,10] aspirin is more than clopidogrel alone, and similar

14 Journal of Digestive Endoscopy ¦ Volume 10 ¦ Issue 1 ¦ January-March 2019 Pal, et al.: Endoscopy and antithrombotics risk with dual antiplatelets is more than aspirin alone. Timing of Procedure Interestingly, statins which are almost always used in Other than balancing risk of GI bleed/procedure and the setting of ACS, lower risk of GI bleed probably by risk of thrombosis on discontinuation of antithrombotic [11,17] increasing gastric mucosal prostaglandin production. agents, important factors to consider are the settings of Minor bleeding is not uncommon during endoscopic endoscopy (elective or urgent). Yet another important procedures, but bleeding is considered to be clinically fact to consider is timing of resumption of antithrombotic significant if hemoglobin falls by >2 g/dl or there is agents after endoscopic hemostasis. Various societies a need for blood transfusion and hospitalization.[11] have developed different guidelines for the management Bleeding can be immediate or delayed up to 2 weeks of those patients. In this review, we shall stress on [3] following the procedure. The odd’s ratio of serious GI Asia‑Pacific guidelines. bleed with aspirin, clopidogrel, and dual antiplatelet Single antiplatelet agent therapy (DAPT) according to a population‑based study Urgent endoscopy is 1.9, 1.8, and 7.4, respectively.[18] Aspirin primarily used for secondary prevention Risk stratification of elective endoscopic procedures of cardiovascular diseases in Asia‑Pacific region including India reduces vascular events and deaths Based on complexity and nature of therapeutic by one‑third and one‑sixth, respectively.[9] Patients intervention, endoscopic procedures can be high with ACS usually require DAPT as all intraplatelet risk (>1% risk of bleeding) or low risk (<1% risk pathways are not blocked by aspirin, a cyclooxygenase of bleeding). These have been listed in Table 5. inhibitor. Other nonaspirin antiplatelets are used Low‑risk procedures do not warrant discontinuation of usually along with aspirin and are hence discussed in antithrombotics (irrespective of type of agent except section of DAPT. for warfarin if INR is supratherapeutic, i.e., >3.5). For high‑risk procedures, anticoagulants and P2Y12 Stopping aspirin antagonists should be discontinued, and aspirin can be Emergency endoscopy should not be delayed in aspirin continued. In high‑risk procedures such as colonoscopic users. If emergency endoscopy is not available, then [3] polypectomy and endoscopic sphincterotomy, aspirin aspirin can be withheld. This is because the effect of [6] has been found to be safe.[19‑21] Few procedures aspirin usually lasts up to 7–9 days after cessation. have ultrahigh risk of bleeding such as endoscopic Resumption of aspirin submucosal dissection (ESD) and endoscopic mucosal Aspirin should be started promptly after endoscopic resection of large polyps (>2 cm) and aspirin should be hemostasis. APAGE/APSDE recommends resumption stopped during these procedures as there is a high risk of of aspirin 3–5 days after hemostasis.[3] ESGE also hemorrhage with continued use of aspirin.[22‑24] Current recommends stopping aspirin for 3 days after APAGE/APSDE guidelines have added an additional treatment of high‑risk stigmata during endoscopic ultrahigh‑risk group which was not included in earlier hemostasis.[9] Available evidence resumption of ASGE guidelines although BSG‑ESGE guidelines have aspirin after nonvariceal upper GI bleed comes from recognized this very high‑risk group but did not stratify a double‑blind placebo‑controlled trial done in Hong this group [Table 1].[3,9,10] Kong by Sung et al. One hundred and fifty‑six aspirin

Table 5: Classification of elective endoscopic procedures according to risk of bleeding Low‑risk procedures (<1%) High‑risk procedures (>1%) Ultrahigh‑risk procedures Diagnostic endoscopy with biopsy Therapeutic endoscopy‑ dilatation of ESD* strictures, injection or banding of varices Therapeutic procedures like esophageal/colonic/enteral PEG/PEG‑J* Ampullectomy EMR* of large polyps (>2 cm) stenting (0.5%-1%) and APC Polypectomy (0.3%-10%) EUS without FNA* EUS + FNA* ERCP* with pancreatic or biliary stunting ERCP* with sphincterotomy±balloon sphincteroplasty Diagnostic push or device‑assisted enteroscopy (0.2%) POEM* Video capsule endoscopy Cystoenterostomy, *endoscopic therapy for Zenker’s diverticulum *POEM=Peroral endoscopic myotomy, EUS=Endoscopic ultrasound, FNA=Fine needle aspiration, EMR=Endoscopic mucosal resection, ESD=Endoscopic submucosal dissection, ERCP=Endoscopic retrograde cholangiopancreatography, PEG/PEG‑J=Percutaneous endoscopic gastrostomy/jejunostomy

JournalJournal of of Digestive Digestive Endoscopy Endoscopy ¦ ¦Volume Volume 10 10 ¦ ¦Issue Issue 1 1 ¦¦ January-March 2019 15 Pal, et al.: Endoscopy and antithrombotics users with cardiovascular disease with actively bleeding can be resumed after 2–3 days. There are no data on GI peptic ulcers were randomized to resume aspirin or procedure risk with new antiplatelet agent vorapaxar, a placebo immediately after endoscopic hemostasis. At protease‑activated receptor 1 antagonist, which is not yet 8 weeks, ten times all‑cause mortality was noted in available in India.[3] nonaspirin users compared to aspirin users. A thirty‑day Elective endoscopy on dual antiplatelet therapy rebleeding rate was two times higher in aspirin For low‑risk procedures, stopping DAPT therapy is not group.[3,25] Hence, resumption of aspirin after treatment recommended. For high‑risk procedures stop P2Y12 of nonvariceal GI bleeding is critical as possibility of inhibitors 5 days before endoscopy and continue aspirin serious cardiovascular outcomes due to nonresumption and resume DAPT after adequate hemostasis. For of aspirin outweigh risk of rebleeding due to resumption ultrahigh‑risk procedures, both antiplatelets should be of aspirin. stopped. For high‑risk procedures, the management of Role of platelet transfusion antithrombotic therapy varies according to thrombotic ASGE guidelines recommend platelet transfusion for risk category: very high, high, and moderate to low life‑threatening GI bleed in patients on aspirin, but [Table 3].[3] As short period of triple antithrombotic available evidence is on the contrary.[10] In a retrospective therapy (DAPT plus anticoagulant) followed by 1 year cohort study, rebreeding rate was similar after platelet of double therapy (DAPT or single antiplatelet and oral transfusion but associated with high mortality.[26] anticoagulant) is often used in patients with ACS/PCI and nonvalvular AF, the management of anticoagulants Elective endoscopy (warfarin and direct‑acting oral anticoagulants (DOACs) For low‑ and high‑risk procedure, aspirin can be is mentioned in Table 3. The status of anticoagulants continued, but it has to be stopped prior to ultrahigh‑risk and endoscopy procedures will be discussed later. procedures [Table 5]. Warfarin Dual antiplatelet therapy Emergency endoscopy Urgent endoscopy Stopping warfarin and reversal of anticoagulation Stopping clopidogrel All the guidelines recommend stopping warfarin in

Given the high risk of stent thrombosis in initial case of serious life‑threatening bleeding.[3,9,10] Reversal 6 months after coronary stent placement, the of anticoagulation is recommended in all patients APAGE/APSDE guidelines recommend discussion on warfarin according to irrespective of INR level with cardiologist before stopping antiplatelet according to ASGE guidelines, but APAGE/APSDE [3,27] therapy. If both antiplatelets are stopped, the median recommends reversal only if INR >2.5. The basis of this time to stent thrombosis is as short as 7 days, whereas recommendation is a very high success rate of endoscopic it is 122 days if only clopidogrel is stopped.[28] This is hemostasis (>95%) if INR is between 1.5 and 2.5.[33,34] the rationale of stopping clopidogrel alone. With higher prevalence (25%) of slow metabolizers of CYP2C19 in Reversal agents Asian population compared to Western population (5%), The options of reversal are four‑factor prothrombin drug interaction of clopidogrel with high‑dose complex concentrate (PCC) or fresh frozen plasma (FFP). proton‑pump inhibitor cannot be ruled out.[3,29] Although The advantages of the former are faster onset of action, not validated, this represents another cause for stopping less fluid overload, lower infection risk, and no need for clopidogrel rather than aspirin in these settings. ABO mismatching. Four‑factor PCC has to be combined with Vitamin K to replenish factor VII as it has a very Resuming clopidogrel and other P2Y12 inhibitors short half‑life (4 h). The optimal dose of Vitamin K for Other P2Y12 inhibitors such as prasugrel (irreversible) reversal is also an area of debate.[35] ASGE recommends and ticagrelor (reversible) are more potent and 5–10 mg of Vitamin K whereas APAGE/APSDE associated with higher bleeding complications. There recommends low‑dose Vitamin K (1–2.5 mg) based on is no head‑to‑head comparison of bleeding risk finding of RCTs which shows that the optimal dose for between prasugrel and ticagrelor. Among DAPTs, the reversal is 1–2.5 mg.[36,37] Low dose is also recommended comparative bleeding risk is as follows: prasugrel + based on the fact that early initiation of warfarin therapy aspirin > ticagrelor+ aspirin > clopidogrel + aspirin.[30‑32] may be required in patients with high thromboembolic The days by which platelet function returns to normal in risk. In patients with high thromboembolic risk, prasugrel, clopidogrel, and ticagrelor are 7 days, 5 days, heparin‑bridging therapy should be started given the and 3–5 days. Hence, reinitiation of prasugrel and slow onset of action of warfarin after reinitiation. ESGE clopidogrel (both irreversible inhibitor) should be done recommends LMWH for bridging therapy, whereas after 5 days, whereas ticagrelor (reversible inhibitor) ASGE and APAGE/APSDE recommend UFH due to its

16 Journal of Digestive Endoscopy ¦ Volume 10 ¦ Issue 1 ¦ January-March 2019 Pal, et al.: Endoscopy and antithrombotics shorter half‑life (1–2 h compared to 4–5 h for LMWH) Severity of bleeding: if bleeding is not life‑threatening, which allows rapid reversal in the event of rebleeding.[38] then temporary discontinuation of DOACs will be Resumption of warfarin sufficient with hemodynamic support. For life‑threatening bleed, antidotes such as activated charcoal, monoclonal The thrombotic risk of individual patient dictates the antibody against dabigatran (idarucizumab 5 gm), or optimal time of resumption of warfarin. Resuming dialysis in case of dabigatran (rest are nondialyzable) warfarin at 7–30 days reduces thromboembolism risk can be used.[40‑42] significantly without increasing bleeding risk but 1. Timing of last DOAC intake: Activated charcoal is resuming <7 days increases rebleeding risk by 2‑fold.[39] effective as antidote if given within the first 3 h as Hence, ESGE guidelines recommend to restart warfarin most DOACs have peak action at 3 h[40] at 7–15 days following bleeding event.[9] Whereas 2. Creatinine clearance: All the DOACs are APAGE/APSDE guidelines recognize that early contraindicated for creatinine clearance below rebleeding risk significantly decreases after day 3, so 15 ml/min. Dabigatran is contraindicated for early resumption of warfarin is recommended at day 3 in patients with high thromboembolic risk as time to creatinine clearance below 30 ml/min re‑anticoagulation may be prolonged.[3] 3. Pharmacokinetic properties of individual DOACs: DOACs have fast onset of action (1–4 h), with Bridging therapy based on risk of thromboembolism a half‑life of 12 h. Eighty percent of dabigatran is Already been discussed earlier in section of risk of eliminated by renal route, and hence, it is dialyzable thrombosis in prothrombotic states. whereas other DOACs are not. Most of the DOACs Direct‑acting oral anticoagulants should be discontinued 2 days before high‑risk Urgent endoscopy endoscopic procedure, except for dabigatran for Stopping direct‑acting oral anticoagulants which time of discontinuation varies according to creatinine clearance [Table 2]. The management of acute bleeding in patients on DOACs is covered in details in APAGE/APSDE The role of FFP or four factor PCC in severe bleeding guidelines, whereas specific recommendations are not with DOACs is doubtful in view of the scarcity of [3,9,10] [5,43] provided by ASGE or ESGE guidelines. clinical data. For management in such situations, the following are to Measurement of anticoagulant activity of DOACs can be be considered. done by specific factor assays as recommended in ESGE

Figure 1: Concise algorithmic management outline of patients on antiplatelet or antithrombotic therapy requiring urgent or elective endoscopy

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Table 6: Comparison and major differences between the existing guidelines APAGE‑APSDE ASGE ESGE Nonvariceal upper GI bleeding Platelet transfusion for Not recommended Considered as an option for An option for patients on life‑threatening bleeding patients on antiplatelets DOACs Patient on DAPT Continue Aspirin, after endoscopic Liaison with cardiologist Continue aspirin, consult hemostasis, withhold 2nd agent for cardiologist for resuming 5 days second antiplatelet agent Patient on warfarin Role of Low‑dose Vitamin K 1-2.5 mg ACCP ‑ 5-10 mg Vitamin K 5-10 mg Vitamin K for reversal Resumption of warfarin By day 3 after hemostasis, high TE By 7-15 days following risk ‑ UFH bridging bleed, no mention about bridging Resumption of DOACs By day 3, no need for bridging Not mentioned Not mentioned Elective endoscopic procedures High bleeding risk Ultrahigh‑risk factors introduced Did not cover ultrahigh‑risk Recognizes ultrahigh‑risk procedures procedures Timing of elective <6 weeks ‑ defer DES with DAPT ‑ Defer up to DES: <12 months endoscopy in ACS/ 6 weeks-6 months ‑ high risk, risk 12 months BMS: <1 month coronary stents independent of type of stent Risky to discontinue second antiplatelet agent Bridge therapy Nonvalvular AF with Nonvalvular AF with Not indicated in nonvalvular CHA2DS2‑VASc>5 CHA2DS2‑VASc >2 AF irrespective of CHA2DS2 VASc score DOACs Low risk ‑ do not omit Same as APAGE‑APSDE, Low risk ‑ omit morning dose High risk ‑ resume after except heparin bridging if of DOACs on the day hemostasis ‑ no heparin bridging resumption not possible within High Risk ‑ delay resumption 12-24 h of DOACs for 24-48 h, no

heparin bridging APAGE=Asian pacific association of gastroenterology, APSDE=Asian Pacific Society for Digestive Endoscopy, ESGE=European Society of Gastrointestinal Endoscopy, ASGE=American Society of Gastroenterology, DOACs=Direct oral anticoagulants, ACS=Acute coronary syndrome guidelines but is not recommended by APAGE/APSDE DOAC even on the day of procedure given very low due to nonavailability issues.[3,9] risk of such procedures.[3,9] Resumption of direct‑acting oral anticoagulants after Triple and double antithrombotic therapies hemostasis As discussed in section of DAPT, in patients with Early resumption without heparin bridging is nonvalvular AF and ACS/PCI, a short period of recommended as these agents have short half‑life (12 h) triple antithrombotic (DAPT + 1 oral anticoagulant) and fast onset of action (1–4 h). Concerns about early followed by dual therapy (single antiplatelet + 1 oral rebleeding should not defer the resumption of DOACs anticoagulant) for up to 1 year is recommended. The as most of the times rebleed can be controlled in a European Society of Cardiology recommends to stop predictable way.[3] one of the antiplatelets during bleed with triple therapy and discontinuation of antiplatelet for bleed during dual Elective endoscopy therapy. In patients with nonvalvular AF and ACS/PCI DOACs should be stopped only before high or and low risk of stroke, they recommend DAPT alone ultrahigh‑risk procedures at least 48 h before for 1 year without anticoagulant.[44] The APAGE/APSDE endoscopy (timing may vary according to creatinine guidelines recommend discussion with a cardiologist in clearance: CrCl) [Table 2]. Bridging anticoagulation this complex situation.[3] is not warranted neither before nor after endoscopic hemostasis with resumption of DOACs after adequate Conclusion hemostasis without undue delay. The literature of endoscopy in patients with For low‑risk procedures, although ESGE guidelines antithrombotic is still evolving, and many of the recommend stopping morning dose of DOACs, recommendations by various societies are based APAGE/APSDE guidelines do not recommend stopping on indirect evidence. The most recent APAGE/

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APSDE guidelines published in 2018 are developed 10. ASGE Standards of Practice Committee, Acosta RD, specifically to meet the needs of Asia‑Pacific region to Abraham NS, Chandrasekhara V, Chathadi KV, Early DS, et al. The management of antithrombotic agents for patients manage patients on antithrombotic who need elective undergoing GI endoscopy. Gastrointest Endosc 2016;83:3‑16. or emergency endoscopy given the higher incidence 11. Foley P, Foley S, Kinnaird T, Anderson RA. Clinical review: of nonvariceal upper GI bleed and more common Gastrointestinal bleeding after percutaneous coronary performance of invasive endoscopic procedures such intervention: A deadly combination. QJM 2008;101:425‑33. as ESD in this region. The comparison with other 12. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, guidelines has been highlighted in Table 6. The main et al. A clinical trial comparing three antithrombotic‑drug regimens after coronary‑artery stenting. Stent anticoagulation aim of this review was to simplify this complex restenosis study investigators. N Engl J Med 1998;339:1665‑71. subject of managing patients on antithrombotics 13. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, requiring endoscopy which has been summarized in Natarajan MK, et al. Effects of pretreatment with clopidogrel Figure 1. and aspirin followed by long‑term therapy in patients undergoing percutaneous coronary intervention: The PCI‑CURE study. Financial support and sponsorship Lancet 2001;358:527‑33. Nil. 14. Moscucci M, Fox KA, Cannon CP, Klein W, López‑Sendón J, Montalescot G, et al. Predictors of major Conflicts of interest bleeding in acute coronary syndromes: The Global Registry of There are no conflicts of interest. acute Coronary Events (GRACE). Eur Heart J 2003;24:1815‑23. 15. Al‑Mallah M, Bazari RN, Jankowski M, Hudson MP. Predictors References and outcomes associated with gastrointestinal bleeding in patients with acute coronary syndromes. J Thromb Thrombolysis 1. Goodman LS, Brunton LL, Chabner B, Knollmann BC. 2007;23:51‑5. Goodman & Gilman’s Pharmacological Basis of Therapeutics. 16. Abbas AE, Brodie B, Dixon S, Marsalese D, Brewington S, New York: McGraw‑Hill; 2011. O’Neill WW, et al. Incidence and prognostic impact of 2. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, th gastrointestinal bleeding after percutaneous coronary intervention Loscalzo J. Harrison’s Principles of Internal Medicine. 19 ed. for acute myocardial infarction. Am J Cardiol 2005;96:173‑6. New York: McGraw Hill Education; 2015. 17. Atar S, Cannon CP, Murphy SA, Rosanio S, Uretsky BF, 3. Chan FK, Goh KL, Reddy N, Fujimoto K, Ho KY, Hokimoto S, Birnbaum Y. Statins are associated with lower risk of et al. Management of patients on antithrombotic agents gastrointestinal bleeding in patients with unstable coronary

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34. Wolf AT, Wasan SK, Saltzman JR. Impact of anticoagulation on Grove EL, et al. Management of antithrombotic therapy after rebleeding following endoscopic therapy for nonvariceal upper bleeding in patients with coronary artery disease and/or atrial gastrointestinal hemorrhage. Am J Gastroenterol 2007;102:290‑6. fibrillation: Expert consensus paper of the European Society 35. Karaca MA, Erbil B, Ozmen MM. Use and effectiveness of of Cardiology Working Group on Thrombosis. Eur Heart J prothrombin complex concentrates vs. fresh frozen plasma in 2017;38:1455‑62.

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